Cotargeting BCL-2 and PI3K induces BAX-dependent mitochondrial apoptosis in AML cells

Mohamed Rahmani, Jewel Nkwocha, Elisa Hawkins, Xinyan Pei, Rebecca E. Parker, Maciej Kmieciak, Joel D. Leverson, Deepak Sampath, Andrea Ferreira-Gonzalez, Steven Grant

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110b-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34 þ /38/123 þ AML cell populations but not in normal hematopoietic progenitor CD34 þ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment–associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK/ cells and failed to induce apoptosis in BAX/ and BAX/BAK/ cells, whereas BIM/ cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML. Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia.

Original languageBritish English
Pages (from-to)3075-3086
Number of pages12
JournalCancer Research
Volume78
Issue number11
DOIs
StatePublished - 1 Jun 2018

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